Butorphanol is a synthetic opioid agonist-antagonist that is highly effective for the treatment of both chronic and acute pain. Parenterally administered butorphanol is more potent than morphine and most other morphine analogs. Butorphanol is metabolized in the liver and excreted by the kidney. The elimination of butorphanol and its metabolites is rapid and the duration of analgesia is usually in the range of three to four hours, with maximal analgesia obtained one-half to one hour following parenteral administration. Butorphanol can be used to treat acute surgical pain, severe post-operative pain and chronic pain. The drug has been shown to be an effective pain management therapy in treating pain associated with numerous types of surgery, burns and kidney stones.
Parenteral formulations of butorphanol and the use of parenteral butorphanol for the relief of acute and chronic pain are known in the art (See, e.g., U.S. Pat. No. 3,819,635). A parenteral formulation of butorphanol is commercially available under the name STADOL.RTM. from Bristol-Meyers Laboratories, Inc. 2-4 mg of that formulation are typically injected intramuscularly for the treatment of post-operative pain. Typically, dosing interval ranges from about three to about four hours are needed to sustain analgesia.
A sustained release formulation of butorphanol encapsulated in phospholipid vesicles or Liposome is disclosed in European Patent Application 0300806A1. In accordance with that disclosure, butorphanol tartrate in phosphate buffered saline is encapsulated with lipid films of distearoylphosphatidylcholine and cholesterol. Effective levels of analgesia ranging from 12 to about 24 hours can be achieved by administering such Liposome encapsulated butorphanol.
South African Patent Application 91/4549 discloses sustained release pharmaceutical formulations and the use of those formulations in delivering therapeutic agents over periods of time of from about 12 to about 24 hours. Formulations disclosed in that South African patent application are microspheres of between 5 to 300 micrometers that contain at least one pharmaceutically active substance contained in a spherical structure formed by at least one pharmacologically inactive carrier substance. The carrier substance is naturally present in the organism to be treated and is stable in the solid state up to a temperature of at least 60.degree. C. Exemplary such carrier substances are coprosterol, glycocholic acid, cholesterol and cholesterol esters. Pharmaceutically active substances that can be administered using such micro spheres are tranquilizers, anti-emetics, vasodialators, antihistiminics, steroids and analgesics.
Existing sustained release formulations are costly and require multi-step manufacturing procedures. There continues to be a need in the art for simple, inexpensive formulations of butorphanol that provide a controlled, sustained release of the drug over long periods of time.